tbuckley/cabot-search huggingface dataset:
CeNtuRIOn: Rucaparib (R) with nivolumab (N) and ipilimumab (I) in patients (pts) with relapsed ovarian cancer (ROC)—Results of an initial safety cohort.
Authors: Marcia Hall, Karen Allan, Agnieszka Michael, Andrew R. Clamp, Rosalind Glasspool, Shibani Nicum, Rosemary Lord, Susana N. Banerjee, Joshua Roche, Jamie Stobo, Charlie Gourley
Journal: Journal of Clinical Oncology (2022)

5577 Background: There is an urgent need to improve outcomes for ROC pts; progression free (PFS)/overall survival (OS) are 4-9 months (mo), 12-20mo respectively. ̃50% ROC pts harbour homologous repair deficiencies (HRD), identified by BRCA mutations (m) &amp; Loss of Heterozygosity (LoH). R, a PARP inhibitor (PARPi) has demonstrated efficacy when used as maintenance after chemotherapy (CT), and is superior to CT if used as treatment for ROC BRCAm pts. However repeating PARPi, even in highly selected BRCAm/HRD pts has limited benefit (1.5-2.5mo extra PFS). Single agent immunotherapy (PD-1/PD-L1/CTLA4 antibodies (Ab)) in ROC pts has been disappointing. Response rate to combined PD-1/CTLA4 Ab in ROC pts is 31.3%. In vitro evidence suggests that combinations of PD-1/CTLA4 Ab /PARPi may be more effective. CeNtuRIOn aims to explore the activity/toxicity of repeat PARPi (R) versus R+I (CTLA4 Ab) versus R+I+N (PD-1 Ab). Here we report safety data from the run-in cohort of 15 ROC pts treated with the triplet combination, RNI. Methods: Eligible pts had received ≥1 and &lt;3 lines CT, were &gt; 3 to &lt;12 months from last platinum CT. Only 1 pt could experience a dose limiting toxicity (DLT) over initial 6 weeks of treatment. Pts received N 240mg q14 days, I 1mg/kg q42 days intravenously for up to 12mo and R orally, 600mg bd continuously. All bar 1 of 7 pts (recruited 06/19–12/19) received N+I to meet DLT evaluability, but 5 of remaining 6 received &lt; 43% R during safety period. 6 further pts were recruited (08/20-06/21), with ≥60% starting dose R in first 6 weeks now required for evaluability. Review of toxicity/tolerability prompted reduction of R starting dose to 400mg bd and ipilimumab limited to 4 cycles for the last 4 pts. Results: Of all 15 recruits, median age was 64. Adverse events (AE)s are detailed in Table. 7 pts were evaluable for safety assessment: n = 4 started on 600mg bd and n = 3 on 400mg bd R. Median R dose intensity in these 7 was 82.5%. There was 1 DLT: G3 nephritis on day 18. 1 pt died of E. Coli sepsis related to colitis. Outcome data will be presented. Conclusions:R (400mg bd)+N+I (4 cycles only) will be taken forward to phase II. Pts will be randomised 1:1:2 to single agent R, R+I or RNI. Pts recruited to R alone are eligible for 2nd randomisation (1:1) to add I or N+I at progression. Clinical trial information: ISRCTN10490346. [Table: see text]
Phase I dose escalation and expansion study of defactinib, pembrolizumab, and gemcitabine in patients with advanced treatment-refractory pancreatic cancer.
Authors: Andrea wang-gillam, Kian-Huat Lim, Robert R. McWilliams, Rama Suresh, A. Craig Lockhart, Amberly Brown, John Herndon, Katrina Sophia Pedersen, Benjamin R. Tan, Nicolas Boice, Mina Abdiannia, Feng Gao, Harry H. Yoon, Mojun Zhu, Nikolaos A. Trikalinos, Lee Ratner, Olivia Aranha, William G. Hawkins, Brett Herzog, David G. DeNardo
Journal: Journal of Clinical Oncology (2022)

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.
FORTITUDE: Results of a phase 1a study of the novel transgene-armed and tumor-selective vector NG-350A with and without pembrolizumab (pembro).
Authors: Lee S. Rosen, D. Ross Camidge, Danny Khalil, Thomas Lillie, Jo Carter, David Krige, Jessica Davies, David Miles, Minesh Patel, Vladimir Evilevitch, Isabel Prieto González-Albo, Brian Champion, Aung Naing
Journal: Journal of Clinical Oncology (2022)

2559 Background: Stimulating CD40 may support anti-cancer immune responses; however, on-target toxicity limits systemic dosing. NG-350A is a tumor-selective and blood stable adenoviral T-SIGn vector expressing a potent fully human IgG agonistic anti-CD40 antibody (mAb). NG-350A was designed to selectively deliver anti-CD40 to multiple tumor sites via IV delivery, driving immunological tumor re-engineering while avoiding systemic toxicity. We report results from a first-in-human trial after completion of enrollment. Methods: FORTITUDE (NCT03852511) is a phase 1 study of NG-350A ± pembro in patients (pts) with metastatic/advanced epithelial tumors. NG-350A monotherapy (mTx) was dose-escalated in separate intratumoral (IT; increasing numbers of doses) or IV (one cycle; three increasing dose levels) cohorts. IV NG-350A + pembro (200 mg Q3W for ≤8 cycles) was then assessed. Results: As of Jan 2022, 28 heavily pre-treated pts had received NG-350A, either as IT mTx (n=9; two dose levels), IV mTx (n=16; IV dose levels 1, 3 &amp; 4) or IV + pembro (n=3; IV dose level 2). The MTD of NG-350A ± pembro was not reached, with no DLTs at the highest IT and IV dose levels. The safety profile of NG-350A was consistent with acute reactions to viral particles and asymptomatic aPTT prolongations (Table). No systemic CD40 transgene protein was detected at any dose level and the only SAE to occur in &gt;1 pt was pneumonia. No objective responses were observed; however, 3/6 patients treated with NG-350A mTx at IV dose level 4 achieved stable disease (dose not yet tested with pembro). Dose-dependent specific increases in serum IL-12, IFNγ and IL-17a were detected in pts treated with IV NG-350A mTx from ̃Wk 2. Increases were sustained at ≥5x baseline levels 7 wks after dosing in the majority of evaluable pts treated at higher IV dose levels. These responses did not occur with IT dosing (or in prior studies with an unarmed vector); further follow-up is ongoing for NG-350A + pembro. IV NG-350A also led to the expansion of T cell clones in blood; most of these were newly detected. Conclusions: NG-350A ± pembro was well-tolerated, with no evidence of CD40-related toxicity. NG-350A IV mTx led to specific and sustained cytokine responses consistent with the MoA of the encoded anti-CD40 Ab. Peak cytokine elevations were typically higher than reported with systemic anti-CD40 Abs, suggesting NG-350A can drive local immunological tumor changes while avoiding systemic toxicity. A further trial (FORTIFY, NCT05165433) will continue dose-escalation of NG-350A + pembro to identify a dose level for efficacy assessments. Clinical trial information: NCT03852511. [Table: see text]
FAST-FNA molecular diagnostic assay facilitates rapid diagnosis and ntrk biomarker testing of salivary gland tumors.
Authors: Sara I. Pai, Juhyun Oh, Tae Yeon Yoo, William C Faquin, Jonathan C.T. Carlson, Talia M. Saal, Daniel G. Deschler, Ralph Weissleder
Journal: Journal of Clinical Oncology (2022)

e18089 Background: Primary epithelial salivary gland tumors (SGTs)are classified into 31 tumor types. Diagnosing SGTs through fine needle aspiration (FNA) biopsies is challenging due to the overlapping cytomorphologic features between benign and malignant tumors. In this study, we developed an innovative, multiplexed cycling technology which allows for the rapid cellular analyses of single cells obtained from FNA which can facilitate the rapid molecular analyses and diagnosis of SGTs. Methods: Antibodies against 29 cell surface markers associated with 7 SGT subtypes were validated and chemically modified via custom linker–bio-orthogonal quencher probes (FAST). Single cell homogenates and a FNA sample set representing 7 SGT subtypes were profiled by FAST cyclic staining, imaging, and automated computational analysis. A prediction model was generated utilizing a training set of 151,926 single cells obtained from primary SGTs (N = 26) and validated on a separate cohort of SGTs (N = 30). Companion biomarker testing, such as NTRK, was also assessed with the FAST technology. Results: The customized FAST-FNA SGT molecular diagnostic and biomarker panel was validated on human cell lines and specificity confirmed by both flow cytometry and clinical immunohistochemical staining on primary SGTs. The FAST molecular diagnostic assay was able to distinguish between benign and malignant SGTs with an accuracy of 0.86 for single-cell suspension samples and 0.88 for FNA samples. Profiling of multiple markers as compared to a single tumor marker increased the diagnostic accuracy of the SGTs, 0.82 as compared to 0.65-0.74, respectively. The results of the assay were highly reproducible and independent of the cell number sampled. NTRK expression in SGTs was also assessed by the FAST assay within hours, highlighting the potential therapeutic application of this technology. Conclusions: High dimensional single-cell profiling and molecular diagnostic testing on FNA samples are feasible at relatively low cost and as a rapid test. Application of the novel multiplexed single cell technology improves the diagnostic accuracy of SGT biopsy and facilitates multiplex biomarker testing from FNA samples. The customizable and modular FAST-FNA approach has relevance to multiple pathologies and organ systems where cytologic samples are often scarce and/or indeterminate resulting in improved diagnostic workflows and timely therapeutic clinical decision making.
Predictors of secondary lung cancer among Hodgkin lymphoma survivors: A nationwide analysis.
Authors: Yanal Mufeed Alnimer, Moaath Khader Mustafa Ali
Journal: Journal of Clinical Oncology (2022)

e19529 Background: There is insufficient data regarding the incidence rate of secondary lung cancer among Hodgkin lymphoma survivors and the predisposing factors. Methods: We analyzed the data from the cohort of subjects who had Hodgkin Lymphoma between 1973 and 2015 using the Surveillance Epidemiology and End Results database (SEER). Data on patient's age, gender, year of diagnosis with Hodgkin lymphoma, Ann-Arbor stage, Histology, racial groups, date of last follow-up, date of death, and treatment modalities were collected. Results: We identified a total of 56,856 subjects with Hodgkin lymphoma; of those, 862 had secondary lung cancer, with an incidence rate of 157 (95%CI: 147-168) per 100,000 person-years. The median overall survival from time of Hodgkin Lymphoma diagnosis for those with secondary lung cancer was 12.1 years (95%CI: 10.7-13) compared to 27.1 years (95%CI: 26.5-27.6) for those who did not develop lung cancer. After propensity score weighting, radiation therapy was associated with a higher risk of secondary lung cancer (HR: 1.23, 95%CI: 1.002-1.55). Older age at the time of Hodgkin lymphoma diagnosis and male gender were associated with higher risk, with an HR of 1.07 (95%CI 1.062-1.073) and an HR of 1.602 (95%CI 1.33-1.94), respectively. Furthermore, chemotherapy increases the risk only among older age groups. Conclusions: Older age at the time of Hodgkin Lymphoma diagnosis, male gender, radiation therapy and chemotherapy only among older age groups were associated with higher risk for secondary lung cancer, with 50% of the cases occurring within 9.1 years following Hodgkin lymphoma diagnosis.[Table: see text]
Maximum somatic allele frequency-adjusted blood-based tumor mutational burden balances the effect of intratumor heterogeneity on response to immune checkpoint Inhibitors in non-small cell lung cancer patients.
Authors: Yiting Dong, Yinpeng Xie, Jie Wang, Zhijie Wang
Journal: Journal of Clinical Oncology (2022)

e21137 Background: ctDNA abundance can influence the accuracy of blood-based tumor mutational burden (bTMB), driving a paradox of bTMB in predicting response and survival benefit of patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) therapy. However, the optimal algorithm of ctDNA adjusted bTMB remains largely unestablished. We aimed to develop a novel approach to optimize the calculation of bTMB by integrating maximum somatic allele frequency (MSAF) to better differentiate the ICI-beneficial NSCLC patients, as well as explore the correlated mechanism. Methods: A 1021-gene panel-based targeted capture sequencing was utilized to evaluate the correlation between MSAF and bTMB based on blood samples in 1679 Chinese NSCLC patients (GCGD database, N = 1679). The establishment of MSAF-adjusted bTMB (Ma-bTMB) was derived from three independent NSCLC cohorts treated with programmed death ligand 1 (PD-L1) or the programmed death 1 (PD-1) inhibitors, including POPLAR cohort (N = 231) as training set, and OAK (N = 642) and Wang (N = 81) cohorts as validation sets separately. PyClone was employed to estimate clonal and subclonal populations. Results: MSAF demonstrated a modest positive correlation between bTMB and MSAF (Spearman’s R = 0.41, P &lt; 0.001, GCGD cohort) and was negatively correlated with survival benefit (Spearman’s rank sum test, overall survival (OS): R = −0.39, P &lt; 0.001; progression-free survival (PFS): R = −0.41, P &lt; 0.001, Wang cohort). Patients with high Ma-bTMB (Ma-bTMB-H) demonstrated improved survival outcomes of anti-PD(L)-1 therapy compared to chemotherapy in POPLAR (PFS, hazard ratio (HR) = 0.63, interaction P = 0.030; OS, HR = 0.44, interaction P = 0.020), which was validated in OAK cohorts (PFS, HR = 0.72, interaction P = 0.040; OS, HR = 0.50, interaction P = 0.010). In addition, Ma-bTMB-H was associated with a better clinical benefit compared to low Ma-bTMB (Ma-bTMB-L) in Wang cohort (PFS, HR = 0.55, P = 0.012; OS, HR = 0.46, P = 0.036). Furthermore, there was a positive correlation between intratumor heterogeneity (ITH) and MSAF (R = 0.37, P &lt; 0.001) in GCGD database, and the effect of ITH on Ma-bTMB (subclones, P = 0.57; subclonal mutations, P = 0.8) was substantially reduced compared to traditional bTMB (subclones, P &lt; 0.001; subclonal mutations, P &lt; 0.001) in Wang cohort. Conclusions: We developed and validated Ma-bTMB, a convenient, readily available, non-invasive predictive biomarker, which reduced the confounding effect of ITH and could effectively differentiate beneficiaries of anti-PD(L)1 therapy, warranting investigation in future clinical trials. Clinical trial information: NCC2018-092.
Design and rationale of a first-in-human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible (irrev), pan-FGFR inhibitor (FGFRi), in adult patients with solid tumors harboring FGFR2 and/or FGFR3 gene alterations (NCT05242822).
Authors: Lipika Goyal, Cesar Augusto Perez, Shumei Kato, Manish Sharma, Benjamin Garmezy, Ken Kobayashi, Aleksandra Franovic, Betty Tam, Cynthia Voong
Journal: Journal of Clinical Oncology (2022)

TPS9601 Background: FGFR1-4 gene alterations are observed in approximately 7% of all human cancers. There are currently 3 FDA-approved, reversible FGFRi for treatment of patients w/previously treated, locally advanced or metastatic (met) cholangiocarcinoma (CCA) harboring FGFR2 gene fusions/rearrangements (pemigatinib and infigratinib) or met urothelial carcinoma (UC) w/susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib). A major limitation of approved and clinical-stage FGFRi is emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response. Up to 67% of CCA patients treated with either reversible or irrev FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irrev, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated w/disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in 28d GLP toxicology studies in rats and beagle dogs and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models in vitro and in vivo. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced &amp; metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given po qd continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approx. 120 pts: Part A is a dose-escalation to MTD for pts w/AMST having either FGFR2 and/or FGFR3 alterations. Part A assesses single agent KIN-3248; Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (ICC, UC, or other AMST), each driven by specified FGFR alterations. Standard Ph1 enrollment criteria are required (ECOG PS 0-1, normal organ function, prior receipt of standard treatment or medical judgment that such is not appropriate). Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. FGFRi-naïve &amp; -pretreated patients are both eligible. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, &amp; duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. Enrollment is expected to commence in April 2022. Clinical trial information: NCT05242822.
Adapted physical activity in patients (Pts) with advanced pancreatic cancer (APACaP): Results from a prospective national randomized GERCOR trial.
Authors: Cindy Neuzillet, Olivier Bouché, Christophe Tournigand, Benoist Chibaudel, Lucile Bouguion, Leila Bengrine-Lefevre, Daniel Lopez-Trabada Ataz, May Mabro, Jean-Philippe Metges, Denis Péré-Vergé, Thierry Conroy, Astrid Lievre, Morgan Andre, Françoise Desseigne, François Goldwasser, Julie Henriques, Amélie Anota, Pascal Hammel
Journal: Journal of Clinical Oncology (2022)

4007 Background: The benefit of adapted physical activity (APA) on health-related quality of life (HRQoL) in Pts with advanced pancreatic ductal adenocarcinoma (aPDAC) treated by chemotherapy (CTx) has never been prospectively assessed. Methods: Pts with aPDAC and ECOG performance status (PS) 0–2 were randomized 1:1 to receive usual care (UC) including first-line CTx at the investigator’s choice (standard arm), or UC plus a home-based 16-week APA program (APA arm). The APA program consisted of personalized aerobic and resistance exercises, with a weekly remote supervision by an APA professional trainer, and unsupervised sessions with a family member or friend (APA partner). The primary objective was the effect on HRQoL at week 16 (W16) measured by 3 dimensions of the EORTC QLQ-C30, global health status (GHS), physical functioning (PF), and fatigue (FA), with a one-sided type I error of 0.016 for each dimension. The primary HRQoL analysis was performed in Pts with available baseline and W16 scores for the 3 targeted dimensions (mITT1). Secondary analyses of HRQoL changes by the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods included Pts with baseline and ≥1 follow-up score (mITT2). Differences &gt; 5 points in scores were considered clinically significant. Results: A total of 313 Pts (median age: 64 years; men: 55%, ECOG PS 0-1: 93%; metastatic: 77%; FOLFIRINOX: 78%, gemcitabine-based: 13%) were included from 11/2014 to 10/2020 (standard arm: n = 157, APA arm: n = 156). In the mITT1 population (n = 172), mean differences in HRQoL at W16 adjusted from baseline were -0.98 (SD 23.87; p = 0.39), -2.08 (SD 21.34; p = 0.26), and 4.16 (SD 29.18; p = 0.18) for GHS, PF, and FA, respectively. In the mITT2 population (n = 259), APA was associated with significant improvements in 5 (GHS, PF, cognitive functioning [CF], social functioning [SF], appetite loss) and 8 (GHS, CF, emotional functioning [EF], SF, insomnia, constipation, pain, financial difficulties) dimensions of HRQoL by MMRM and TUDD, respectively (Table). Secondary endpoints, including overall survival, progression-free survival, and chemotherapy toxicity will be presented. Conclusions: APA in combination with usual care improved several dimensions of HRQoL in Pts with aPDAC receiving first-line CTx. Clinical trial information: NCT02184663. [Table: see text]